July 9, 2010 — The investigational drug olaparib (AstraZeneca) produces significant response rates in patients with ovarian or breast cancer associated with BRCA1 or BRCA2 mutations — even those with 3 previous chemotherapy regimens and platinum resistance.
The finding comes from 2 phase 2 trials with the oral poly(ADP-ribose) polymerase (PARP) inhibitor, which were reported at this year's annual meeting of the American Society of Clinical Oncology and were published online July 6 in the Lancet.
The studies — one in recurrent ovarian cancer (n = 57) and the other in advanced breast cancer (n = 54) — both funded by AstraZeneca, compared high and low doses of oral olaparib in cohorts of women with confirmed genetic BRCA1 or BRCA2 mutations. Patients in these nonrandomized trials were enrolled in sequential cohorts, which had the unfortunate result in the ovarian cancer study of having women in the low-dose group with somewhat worse prognostic factors than those in the high-dose group.
The first cohort in each study was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort was given continuous oral olaparib at 100 mg twice daily. The primary efficacy end point for both trials was objective response rate (ORR).
In the ovarian cancer study, ORR was 33% (11 of 33 patients) in the high-dose cohort and 13% (3 of 24) in the low-dose cohort.
In the breast cancer study, ORR was 41% (11of 27 patients) in the high-dose cohort and 22% (6 of 27) in the low-dose cohort.
In the high-dose cohort, the most common adverse events were fatigue, nausea, vomiting, and anemia; in the low-dose cohort, they were mild nausea and fatigue.
I was surprised at the significant response rates.
"I was surprised at the significant response rates in ovarian (33%) and breast cancer (41%) with BRCA mutations, despite extensive previous chemotherapy, and the relatively mild side-effect profile," said lead author of the ovarian cancer study, M. William Audeh, MD, from the Samuel Oschin Cancer Institute at Cedars-Sinai Medical Center in Los Angeles, California.
Dr. Audeh told Medscape Medical News that these data support the concept of targeting the underlying genetic weakness of cancer, regardless of its organ of origin. "Ovarian cancer, like breast cancer, develops through the dysfunction of many molecular pathways, so ovarian cancer, like breast cancer, is not one disease, but many. The design of trials and the selection of therapy may be better informed by understanding biologically meaningful subsets and targeting their molecular vulnerabilities. These data suggest that for the subset of ovarian cancers with BRCA mutations, inhibition of the PARP enzyme may be a useful therapeutic strategy, but more studies are needed, of course," he said.
In the paper, Dr. Audeh and colleagues write: "These results of this phase 2 study show that the oral PARP inhibitor olaparib, given as monotherapy at a dose of 400 mg twice daily, has antitumor activity in heavily pretreated carriers of the BRCA1 or BRCA2 mutation who have recurrent ovarian cancer. Olaparib 100 mg twice daily also had clinical activity in this population, but this dose seems to be less efficacious than the 400 mg twice daily dose. However, the allocation of patients to these doses was not randomized and the olaparib 100 mg cohort had poorer prognostic features than did the 400 mg cohort."
The authors conclude that these findings "provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer" and support the use of underlying genetic defect rather than organ of origin in selecting cancers for specific targeted therapies.
"In our study, results suggest that PARP inhibition has a wide therapeutic window and sufficient tumor cell selectivity to target ovarian cancers that have defects in DNA repair by homologous recombination. These findings support the hypothesis that BRCA-mutated tumors are susceptible to a synthetic lethal therapeutic approach. These data also support the use of a BRCA1 or BRCA2 mutation as a predictive biomarker for responsiveness to PARP inhibition, and raise the possibility that homologous recombination defects caused by loss of function of other genes with roles in this DNA repair process, or by epigenetic loss of BRCA1 or BRCA2, can predict similar responsiveness to PARP inhibition in a broad, genetically defined group of malignant diseases," Dr. Audeh said.
Andrew Tutt, MD, from the Breakthrough Breast Cancer Research Unit at King's College London School of Medicine in the United Kingdom, who led the international team that conducted both studies and is first author on the breast cancer study, said that the phase 2 study shows that "the oral PARP inhibitor olaparib at 400 mg twice daily was active even in women with BRCA1 or BRCA2 mutations and advanced breast cancer that was resistant to conventional chemotherapy" and provides proof of concept for targeting the DNA repair pathway associated with BRCA1 or BRCA2 in patients with breast cancer.
The results of this and subsequent studies might change established practice.
"Currently, the presence of mutations in BRCA1 or BRCA2 does not inform systemic therapy recommendations for women with breast cancer, but the results of this and subsequent studies might change established practice," Dr. Tutt said.
The researchers also note that the 41% ORR for olaparib and toxicity in the high-dose cohort compares favorably with the expected 20% to 30%, or lower, ORR and toxicity associated with conventional agents. They also noted that a response to olaparib was seen not only in patients with the least number of types of previous chemotherapy, which suggests that resistance to PARP does not overlap resistance to other chemotherapy agents.
The authors conclude that "the results of the study support further investigation of this approach that combines inhibition of a DNA repair target with an inherent residual loss of function of specialized DNA repair in many of these tumors." They plan to test this approach in a broader group of sporadic breast and ovarian cancers that might have inactivation of the homologous recombination repair pathway.
The olaparib studies were supported by AstraZeneca. Some of the investigators in the studies might benefit financially from patents held on PARP inhibitors. Other investigators are employees of the drug company involved.
Lancet. Published online July 6, 2010.
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